This invention relates to a novel class of compounds which exhibit analgesic activity upon parenteral administration.
Recently, endogenous substances having morphine-like properties have been extracted from mammalian brain or csf. These substances, named enkephalin, have been identified by Hughes et al., Nature, 258, 577 (1975) as pentapeptides having the following sequences:
H-Tyr-Gly-Gly-Phe-Met-OH PA0 H-Tyr-Gly-Gly-Phe-Leu-OH. PA0 Abu--.alpha.-aminobutyric acid PA0 Ala--alanine PA0 Cys--cysteine PA0 Gly--glycine PA0 Hse--homoserine PA0 Ile--isoleucine PA0 Leu--leucine PA0 Met--methionine PA0 Nle--norleucine PA0 Nva--norvaline PA0 Phe--phenylalanine PA0 Ser--serine PA0 Tyr--tyrosine PA0 Val--valine PA0 Ac--acetyl PA0 Me--methyl PA0 Et--ethyl PA0 Ip--isopropyl PA0 Pr--n-propyl PA0 Bu--n-butyl PA0 i-Bu--isobutyl PA0 t-Bu--t-butyl PA0 s-Bu--sec-butyl PA0 BOC--t-butyloxycarbonyl PA0 Bzl--benzyl PA0 DCC--N,N'-dicyclohexylcarbodiimide PA0 HBT--1-hydroxybenzotriazole PA0 DMF--N,N-dimethylformamide PA0 TFA--trifluoroacetic acid PA0 THF--tetrahydrofuran PA0 DEAE--diethylaminoethyl PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Abu-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Abu-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Nva-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Nva-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Val-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Val-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Nle-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Nle-Gly-L-Phe-L-(N-Et)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-Gly-L-Phe-L-(N-Pr)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ile-Gly-L-Phe-L-Met-NH.sub.2 PA0 H-L-Tyr-D-Ile-Gly-L-Phe-L-(N-Pr)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Pr)Met-NH.sub.2 : PA0 H-L-Tyr-D-Ala-D-Ala-L-Phe-L-(N-Pr)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Abu-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Nva-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Leu-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Ile-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ile-L-Phe-L-(N-Et)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Val-L-Ala-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-L-Ala-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-tyr-D-Val-L-Val-L-Phe-L-(N-Et)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-L-Leu-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Nle-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Hse(Me)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Nle-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Hse(Me)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)(3-methoxypropyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-NH(3-methoxypropyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)(3-methylthiopropyl); PA0 H-L-Tyr-D-Ala-Gly-Phe-NH(3-methylthiopropyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)(n-pentyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-NH(n-pentyl); PA0 H-L-Tyr-D-(N-Me)Ala-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ala-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ala-L-Ala-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ala-L-Ala-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Et)Ala-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Val-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Leu-Gly-L-Phe-L-(N-Me)Nle-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ile-L-Ala-L-Phe-L-(N-Me)Hse(Me)NH.sub.2 ; PA0 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Nle-L-Nva-L-Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Abu-L-Abu-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-L-Met-NH.sub.2 ; PA0 (N,N-Di-Me)-L-Tyr-D-Ala-L-Ala-L-Phe-L-(N-Me)-Met-NH.sub.2 ; PA0 (N-Allyl)-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 (N-Et)-L-Tyr-D-Abu-L-Ala-L-Phe-L-(N-Et)Nle-NH.sub.2 ; PA0 (N,N-di-Pr)-L-Tyr-D-Val-L-Ala-L-Phe-L-(N-Me)-Hse(Me)-NH.sub.2 ; PA0 (N-Pr)-L-Tyr-D-Leu-Gly-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 (N,N-Di-Et)-L-Tyr-D-(N-Pr)Abu-L-Ala-L-Phe-L-Met-NH.sub.2 ; PA0 (N-Me,N-Et)-L-Tyr(Ac)-D-(N-Pr)Nle-L-Ala-L-Phe-L-(N-Me)Met-NH.sub.2 ; PA0 (N,N-Di-Me)-L-Tyr(Ac)-D-(N-Et)Ile-L-Val-L-Phe-L-(N-Pr)Met-NH.sub.2 ; PA0 (N-Me)-L-Tyr(Ac)-D-(N-Me)Leu-Gly-L-Phe-L-(N-Et)-Nle-NH.sub.2 ; PA0 (N-Me)-L-Tyr(Ac)-D-(N-Me)Nva-L-Nva-L-Phe-L-(N-Me)Hse(Me)-NH.sub.2 ; PA0 (N-Me)-L-Tyr-D-(N-Me)Ala-L-Nva-L-Phe-NH(3-methoxypropyl); PA0 (N-Et)-L-Tyr(Ac)-D-(N-Me)Abu-Gly-L-Phe-NH(3-methylthiopropyl); PA0 (N-Pr)-L-Tyr(Ac)-D-(N-Me)Val-L-Leu-L-Phe-NH(n-pentyl); PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Et)Phe-L-(N-Me)Nle-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-L-(N-Me)Hse(Me)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-(N-Me)Phe-L-Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-(N-Et)Phe-L-(N-Me)Met-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Val-L-(N-Me)Phe-NH(n-pentyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Met-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Met-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Met-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Met-NH(Et); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Met-NH(Et); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Nle-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Met-NH(Pr); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Pr)Met-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Met-NH(Pr); PA0 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Met-NH(Et); PA0 (N,N-Di-Me)-L-Tyr-D-(N-Me)Ala-Gly-L-(N-Me)Phe-L-(N-Me)Met-NH.sub.2 ; PA0 (N,N-Di-Et)-L-Tyr-D-(N-Me)Ala-Gly-L-(N-Et)Phe-L-(N-Et)Met-NH(Me); PA0 (N-allyl)-L-Tyr-D-(N-Me)Ala-L-Ala-L-(N-Me)Phe-L-(N-Me)Nle-NH(Me); PA0 (N-Me)-L-Tyr-D-Ala-L-Val-L-(N-Me)Phe-L-(N-Pr)-Hse(Me)-NH(Me); PA0 (N,N-Di-Me)-L-Tyr-D-Val-L-Ala-L-(N-Me)Phe-L-(N-Me)Met-NH(Me); PA0 (N,N-Di-Pr)-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-L-(N-Me)Met-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-L-Met-NH(Me); PA0 (N-Me)-L-Tyr-D-Ala-L-Abu-L-(N-Et)Phe-N(Et)(3-methoxypropyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Pr)(3-methylthiopropyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Pr)(n-pentyl); PA0 (N,N-Di-Me)-L-Tyr(Ac)-D-(N-Pr)Ala-Gly-L-(N-Et)-Phe-L-(N-Me)Met-N(Di-Me); PA0 (N,N-Di-Pr)-L-Tyr(Ac)-D-(N-Et)Val-L-Nva-L-(N-Me)Phe-L-(N-Me)Met-NH(Me); PA0 (N-allyl)-L-Tyr(Ac)-D-(N-Pr)Ile-L-Nle-L-(N-Pr)-Phe-L-(N-Pr)Nle-NH(Et); PA0 (N-Me)-L-Tyr(Ac)-D-(N-Pr)Leu-L-Abu-L-(N-Me)Phe-L-(N-Me)Hse(Me)-NH(Pr); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Ser(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Abu-Gly-L-Phe-L-Cys(p-methoxy-Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Abu-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Nva-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Nva-Gly-L-Phe-L-Ser(p-methoxy-Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Val-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Val-Gly-L-Phe-L-Ser(Me)-NH.sub.2 ; PA0 H-L-Tyr-D-Nle-Gly-L-Phe-L-Cys(Me)-NH.sub.2 ; PA0 H-L-Tyr-D-Nle-Gly-L-Phe-L-(N-Et)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-Gly-L-Phe-L-Ser(Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-Gly-L-Phe-L-(N-Pr)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ile-Gly-L-Phe-L-Cys(Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Ile-Gly-L-Phe-L-(N-Pr)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Pr)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-D-Ala-L-Phe-L-(N-Pr)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-Phe-L-Ser(Pr)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Abu-L-Phe-L-Ser(Ip)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Nva-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Leu-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ile-L-Phe-L-Cys(i-Bu)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ile-L-Phe-L-(N-Et)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Val-L-Ala-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-L-Ala-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Val-L-Val-L-Phe-L-(N-Et)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Leu-L-Leu-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Ser(p-methoxy-Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Cys(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Ser(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Cys(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)(3-methylbutyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-NH(2-ethoxyethyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)(3-methylbutyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-NH(2-ethylthioethyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)[2-(p-methoxybenzyloxy)-ethyl]; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-NH[2-(p-methoxybenzylthio)ethyl]; PA0 H-L-Tyr-D-(N-Me)Ala-Gly-L-Phe-L-Ser(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ala-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ala-L-Ala-L-Phe-L-Cys(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ala-L-Ala-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Et)Ala-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Val-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Leu-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-(N-Me)Ile-L-Ala-L-Phe-L-(N-Me)Ser(p-chloro-Bzl)-NH.sub.2 ; PA0 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-L-Ser(m-trifluoromethyl-Bzl)-NH.sub.2 ; PA0 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Nle-L-Nva-L-Phe-L-Cys(o-methyl-Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Abu-L-Abu-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-L-Ser(p-methoxy-Bzl)-NH.sub.2 ; PA0 (N,N-Di-Me)-L-Tyr-D-Ala-L-Ala-L-Phe-L-(N-Me)-Leu-NH.sub.2 ; PA0 (N-Allyl)-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 (N-Et)-L-Tyr-D-Abu-L-Ala-L-Phe-L-(N-Et)Leu-NH.sub.2 ; PA0 (N,N-di-Pr)-L-Tyr-D-Val-L-Ala-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 (N-Pr)-L-Tyr-D-Leu-Gly-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 (N,N-Di-Et)-L-Tyr-D-(N-Pr)Abu-L-Ala-L-Phe-L-Leu-NH.sub.2 ; PA0 (N-Me,N-Et)-L-Tyr(Ac)-D-(N-Pr)Nle-L-Ala-L-Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 (N,N-Di-Me)-L-Tyr(Ac)-D-(N-Et)Ile-L-Val-L-Phe-L-(N-Pr)Leu-NH.sub.2 ; PA0 (N-Me)-L-Tyr(Ac)-D-(N-Me)Leu-Gly-L-Phe-L-(N-Et)-Leu-NH.sub.2 ; PA0 (N-Me)-L-Tyr(Ac)-D-(N-Me)Nva-L-Nva-L-Phe-L-(N-Me)Ser(t-Bu)-NH.sub.2 ; PA0 (N-Me)-L-Tyr-D-(N-Me)Ala-L-Nva-L-Phe-NH(2-ethylthioethyl); PA0 (N-Et)-L-Tyr(Ac)-D-(N-Me)Abu-Gly-L-Phe-NH(2-methylthioethyl); PA0 (N-Pr)-L-Tyr(Ac)-D-(N-Me)Val-L-Leu-L-Phe-N(Me)(3-methylbutyl); PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-L-Ser(s-Bu)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Et)Phe-L-(N-Me)Cys(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-L-(N-Me)Cys(p-methoxy-Bzl)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-(N-Me)Phe-L-Ser(Et)-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Ala-L-(N-Et)Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 H-L-Tyr-D-Ala-L-Val-L-(N-Me)Phe-NH(2-ethylthioethyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Ser(Et)-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Leu-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH(Et); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Leu-NH(Et); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Et)Cys(p-bromo-Bzl)NH(Pr); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Pr)Leu-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-L-Cys(Ip)-NH(Pr); PA0 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-L-(N-Me)Leu-NH(Et); PA0 (N,N-Di-Me)-L-Tyr-D-(N-Me)Ala-Gly-L-(N-Me)Phe-L-(N-Me)Leu-NH.sub.2 ; PA0 (N,N-Di-Et)-L-Tyr-D-(N-Me)Ala-Gly-L-(N-Et)Phe-L-(N-Et)Leu-NH(Me); PA0 (N-allyl)-L-Tyr-D-(N-Me)Ala-L-Ala-L-(N-Me)Phe-L-(N-Me)Leu-NH(Me); PA0 (N-Me)-L-Tyr-D-Ala-L-Val-L-(N-Me)Phe-L-(N-Pr)-Ser(Bzl)-NH(Me); PA0 (N,N-Di-Me)-L-Tyr-D-Val-L-Ala-L-(N-Me)Phe-L-(N-Me)Leu-NH(Me); PA0 (N,N-Di-Pr)-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-L-(N-Me)Leu-NH(Me); PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-L-Ser(Pr)-NH(Me); PA0 (N-Me)-L-Tyr-D-Ala-L-Abu-L-(N-Et)Phe-N(Et)(3-methylbutyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Pr)(3-methylbutyl); PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N(Pr)(2-ethoxyethyl); PA0 (N,N-Di-Me)-L-Tyr(Ac)-D-(N-Pr)Ala-Gly-L-(N-Et)-Phe-L-(N-Me)Leu-N(Di-Me); PA0 (N,N-Di-Pr)-L-Tyr(Ac)-D-(N-Et)Val-L-Nva-L-(N-Me)Phe-L-(N-Me)Leu-NH(Me); PA0 (N-allyl)-L-Tyr(Ac)-D-(N-Pr)Ile-L-Nle-L-(N-Pr)-Phe-L-(N-Pr)Leu-NH(Et); PA0 (N-Me)-L-Tyr(Ac)-D-(N-Pr)Leu-L-Abu-L-(N-Me)Phe-L-(N-Me)Leu-NH(Pr); PA0 N-[3-(methylthio)propyl]N-methylamine, PA0 N-[3-(methylthio)propyl]-N-ethylamine, PA0 N-[3-(methylthio)propyl]-N-propylamine, PA0 N-[3-(methoxy)propyl]-N-methylamine, PA0 N-[3-(methoxy)propyl]-N-ethylamine, PA0 N-[3-(methoxy)propyl]-N-propylamine, PA0 N-n-pentyl-N-propylamine, PA0 N-n-pentyl-N-ethylamine, PA0 N-n-pentyl-N-methylamine, PA0 N-(3-methylbutyl)-N-methylamine, PA0 N-(3-methylbutyl)-N-ethylamine, PA0 N-(3-methylbutyl)-N-propylamine, PA0 2-ethoxyethylamine, PA0 2-methoxyethylamine, PA0 2-propoxyethylamine, PA0 2-butoxyethylamine, PA0 2-benzyloxyethylamine, PA0 2-(p-methoxy)benzyloxyethylamine, PA0 2-methylthioethylamine PA0 2-ethylthioethylamine, PA0 2-propylthioethylamine, PA0 2-benzylthioethylamine, PA0 2-(p-methoxy)benzylthioethylamine, PA0 N-methyl-N-(2-ethoxyethyl)amine, PA0 N-methyl-N-(2-ethylthio)ethylamine, PA0 N-methyl-N-(2-benzyloxy)ethylamine, PA0 N-methyl-N-(2-p-methoxybenzyloxy)ethylamine, PA0 N-methyl-N-(2-p-methoxybenzylthio)ethyl, and the like.
These compounds are referred to as methionine-enkephalin and leucine-enkephalin, respectively.
Although these compounds have been shown to exhibit analgesic activity in mice upon administration intracerebroventricularly [Buscher et al., Nature, 261, 423 (1976)], they are practically devoid of any useful analgesic activity when administered parenterally.
A novel class of compounds has now been discovered. These compounds exhibit significant and demonstrable analgesic activity when administered systemically. It is to this class of compounds that this invention is directed.